Inflammation and hypersensitivity in the context of the sensory functions of axonal membranes: what are the molecular mechanisms?
Abstract
BACKGROUND: The axonal membrane of unmyelinated sensory nerve fibers is well equipped with different molecular transducer molecules that establish specific sensitivities, the capacity for sensitization by inflammation and generation of ectopic action potentials that contribute to spinal sensitization, leading to projected pain, allodynia and hyperalgesia. METHODS: We studied the sensory properties of unmyelinated axons in the midnerve by measuring stimulated neuropeptide release, recording from primary afferents and eliciting projected pain by stimulation of a surgically exposed superficial radial nerve in a conscious human subject. RESULTS: Capsaicin (TRPV1) receptor channels are expressed along the axonal membrane and respond to acidic, thermal and capsaicin stimulation with a graded and calcium-dependent calcitonin gene-related peptide release. These responses can be facilitated by bradykinin or prostaglandin, indicating functional BK and EP receptors along the axonal membrane. Sensitizing effects are lost in preparations from TRPV1 knockout mice. In the isolated vagus nerve, representing visceral innervation, the endovanilloid/endocannabinoid anandamide induced or sensitized calcitonin gene-related peptide release by activation of TRPV1. Our electrophysiological recordings revealed ectopic generation of action potentials. Intact unmyelinated axons showed sensory capacities that resembled those of their individual cutaneous nociceptive terminals, with respect to noxious heat sensitivity. In the human subject, noxious heat stimulation of the exposed skin nerve evoked intense burning pain sensation in the innervation territory. CONCLUSION: Different lines of evidence indicate that nociceptive axons exhibit essential parts of the signal transduction and spike generation machinery. When amplified (e.g. by inflammatory mediators), this axonal sensitivity may become a source of neuropathic pain.
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Visceral C-fibers that are sensitized in association with an initial inflammation may become a source of neuropathic pain.
“it has been argued that visceral C-fibers that are sensitized in association with an initial inflammation “may become a source of neuropathic pain” [22].”
From Sprouted Innervation into Uterine Transplants Contributes to the Development of Hyperalgesia in a Rat Model of Endometriosis (2012) · cites this paper as [22]
Cites
1 retracted
Ahluwalia, J., Yaqoob, M., Urbán, L., Bevan, S., & Nagy, I. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.01550.x · Cited by 82 · see citing works
RetractedThe Cloned Capsaicin Receptor Integrates Multiple Pain-Producing Stimuli
Tominaga, M., Caterina, M. J., Malmberg, A. B., Rosen, T. A., Gilbert, H., Skinner, K., Raumann, B. E., Basbaum, A. I., & Julius, D. J. (1998) · Neuron · doi:10.1016/s0896-6273(00)80564-4 · Cited by 3,086 · see citing works
Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide
Zygmunt, P. M., Petersson, J., Andersson, D. A., Chuang, H.-H., Sørgård, M., Di Marzo, V., Julius, D., & Högestätt, E. D. (1999) · Nature · doi:10.1038/22761 · Cited by 2,142 · see citing works
TRPA1 Mediates the Inflammatory Actions of Environmental Irritants and Proalgesic Agents
Bautista, D. M., Jordt, S. E., Nikai, T., Tsuruda, P. R., Read, A. J., Poblete, J., Yamoah, E. N., Basbaum, A. I., & Julius, D. J. (2006) · Cell · doi:10.1016/j.cell.2006.02.023 · Cited by 1,921 · see citing works
Noxious Cold Ion Channel TRPA1 Is Activated by Pungent Compounds and Bradykinin
Bandell, M., Story, G. M., Hwang, S. W., Viswanath, V., Eid, S. R., Petrus, M. J., Earley, T. J., & Patapoutian, A. (2004) · Neuron · doi:10.1016/s0896-6273(04)00150-3 · Cited by 1,822 · see citing works
The Vanilloid Receptor: A Molecular Gateway to the Pain Pathway
Caterina, M. J., & Julius, D. J. (2001) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.24.1.487 · Cited by 1,571 · see citing works
Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines
Macpherson, L. J., Dubin, A. E., Evans, M. J., Marr, F., Schultz, P. G., Cravatt, B. F., & Patapoutian, A. (2007) · Nature · doi:10.1038/nature05544 · Cited by 1,112 · see citing works
Leeb-Lundberg, L. M. F., Marceau, F., Müller‐Esterl, W., Pettibone, D. J., & Zuraw, B. L. (2005) · Pharmacological Reviews · doi:10.1124/pr.57.1.2 · Cited by 942 · see citing works
Induction of vanilloid receptor channel activity by protein kinase C
Premkumar, L. S., & Ahern, G. P. (2000) · Nature · doi:10.1038/35050121 · Cited by 801 · see citing works
Trevisani, M., Siemens, J., Materazzi, S., Bautista, D. M., Nassini, R., Campi, B., Imamachi, N., Andrè, E., Patacchini, R., Cottrell, G. S., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0705923104 · Cited by 775 · see citing works
Anandamide and vanilloid TRPV1 receptors
Ross, R. A. (2003) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0705467 · Cited by 603 · see citing works
Cannabinoid receptors and their ligands
Pertwee, R. G., & Ross, R. A. (2002) · Prostaglandins Leukotrienes and Essential Fatty Acids · doi:10.1054/plef.2001.0341 · Cited by 558 · see citing works
Kinin receptors in pain and inflammation
Couture, R., Harrisson, M., Vianna, R. M. J., & Cloutier, F. (2001) · European Journal of Pharmacology · doi:10.1016/s0014-2999(01)01318-8 · Cited by 472 · see citing works
Breathtaking TRP Channels: TRPA1 and TRPV1 in Airway Chemosensation and Reflex Control
Bessac, B. F., & Jordt, S. (2008) · Physiology · doi:10.1152/physiol.00026.2008 · Cited by 431 · see citing works
Multiple sodium channels and their roles in electrogenesis within dorsal root ganglion neurons
Rush, A. M., Cummins, T., & Waxman, S. G. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2006.121483 · Cited by 427 · see citing works
Specific Involvement of PKC-ε in Sensitization of the Neuronal Response to Painful Heat
Cesare, P., Dekker, L. V., Sardini, A., Parker, P. J., & McNaughton, P. A. (1999) · Neuron · doi:10.1016/s0896-6273(00)80813-2 · Cited by 405 · see citing works
Bradykinin Lowers the Threshold Temperature for Heat Activation of Vanilloid Receptor 1
Sugiura, T., Tominaga, M., Katsuya, H., & Mizumura, K. (2002) · Journal of Neurophysiology · doi:10.1152/jn.2002.88.1.544 · Cited by 313 · see citing works
Kinins in pain and inflammation
Calixto, J. Β., Cabrini, D. A., Ferreira, J., & Campos, M. M. (2000) · Pain · doi:10.1016/s0304-3959(00)00335-3 · Cited by 293 · see citing works
Taylor‐Clark, T. E., Undem, B. J., MacGlashan, D. W., Ghatta, S., Carr, M., & McAlexander, M. A. (2007) · Molecular Pharmacology · doi:10.1124/mol.107.040832 · Cited by 287 · see citing works
Zhang, X., Li, L., & McNaughton, P. A. (2008) · Neuron · doi:10.1016/j.neuron.2008.05.015 · Cited by 275 · see citing works
Endovanilloid signaling in pain
Marzo, V. D. (2002) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(02)00340-9 · Cited by 272 · see citing works
Calixto, J. Β., Medeiros, R., Fernandes, E. S., Ferreira, J., Cabrini, D. A., & Campos, M. M. (2004) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0706012 · Cited by 258 · see citing works
Taylor‐Clark, T. E., McAlexander, M. A., Nassenstein, C., Sheardown, S. A., Wilson, S., Thornton, J., Carr, M., & Undem, B. J. (2008) · The Journal of Physiology · doi:10.1113/jphysiol.2008.153585 · Cited by 237 · see citing works
Vanilloid receptor 1 expression in the rat urinary tract
Avelino, A., Cruz, C. D., Nagy, I., & Cruz, F. (2002) · Neuroscience · doi:10.1016/s0306-4522(01)00496-1 · Cited by 236 · see citing works
PETROCELLIS, L. D., Harrison, S., Bisogno, T., Tognetto, M., Brandi, I., Smith, G., Creminon, C., Davis, J. B., Geppetti, P., & Marzo, V. D. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00406.x · Cited by 199 · see citing works
Schnizler, K., Shutov, L. P., Kanegan, M. J. V., Merrill, M. A., Nichols, B., McKnight, G. S., Strack, S., Hell, J. W., & Usachev, Y. M. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.0233-08.2008 · Cited by 180 · see citing works
Roles of transient receptor potential channels in pain
Stucky, C. L., Dubin, A. E., Jeske, N. A., Malin, S. A., McKemy, D. D., & Story, G. M. (2009) · Brain Research Reviews · doi:10.1016/j.brainresrev.2008.12.018 · Cited by 176 · see citing works
Fajardo, O., Meseguer, V., Belmonte, C., & Viana, F. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.1696-08.2008 · Cited by 174 · see citing works
Kollárik, M., & Undem, B. J. (2003) · The Journal of Physiology · doi:10.1113/jphysiol.2003.054890 · Cited by 154 · see citing works
Role of TRPV receptors in respiratory diseases
Jia, Y., & Lee, L. (2007) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2007.01.013 · Cited by 136 · see citing works
Understanding the signaling and transmission of visceral nociceptive events
Cerveró, F., & Laird, J. M. A. (2004) · Journal of Neurobiology · doi:10.1002/neu.20084 · Cited by 135 · see citing works
A Role for TRPV1 in Bradykinin-Induced Excitation of Vagal Airway Afferent Nerve Terminals
Carr, M. J., Kollárik, M., Meeker, S., & Undem, B. J. (2003) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.102.043422 · Cited by 127 · see citing works
Sauer, S. K., Bove, G. M., Averbeck, B., & Reeh, P. W. (1999) · Neuroscience · doi:10.1016/s0306-4522(98)00731-3 · Cited by 122 · see citing works
Self-citationChapter 15 Anandamide and the Vanilloid Receptor (TRPV1)
Tóth, A., Blumberg, P. M., & Boczán, J. (2009) · Vitamins and hormones · doi:10.1016/s0083-6729(09)81015-7 · Cited by 109 · see citing works
Michaelis, M., Blenk, K.-H., Jänig, W., & Vogel, C. (1995) · Journal of Neurophysiology · doi:10.1152/jn.1995.74.3.1020 · Cited by 103 · see citing works
Bernardini, N., Neuhuber, W., Reeh, P. W., & Sauer, S. K. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2004.03.017 · Cited by 93 · see citing works
Self-citationMoalem‐Taylor, G., Grafe, P., & Tracey, D. J. (2005) · Neuroscience · doi:10.1016/j.neuroscience.2005.05.046 · Cited by 90 · see citing works
Excitation and sensitization of nociceptors by bradykinin: what do we know?
Mizumura, K., Sugiura, T., Katanosaka, K., Banik, R. K., & Kozaki, Y. (2009) · Experimental Brain Research · doi:10.1007/s00221-009-1814-5 · Cited by 87 · see citing works
Bradykinin and peripheral sensitization
Wang, H., Ehnert, C., Brenner, G. J., & Woolf, C. J. (2006) · Biological Chemistry · doi:10.1515/bc.2006.003 · Cited by 78 · see citing works
Pethö, G., Derow, A., & Reeh, P. W. (2001) · European Journal of Neuroscience · doi:10.1046/j.0953-816x.2001.01651.x · Cited by 63 · see citing works
Self-citationNociceptor excitation by thermal sensitization — A hypothesis
Reeh, P. W., & Pethö, G. (2000) · Progress in brain research · doi:10.1016/s0079-6123(00)29004-3 · Cited by 61 · see citing works
Self-citationFischer, M. J. M., Reeh, P. W., & Sauer, S. K. (2003) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2003.02811.x · Cited by 60 · see citing works
Self-citationThe Functional Regulation of TRPV1 and Its Role in Pain Sensitization
Wang, Y. (2008) · Neurochemical Research · doi:10.1007/s11064-008-9750-5 · Cited by 55 · see citing works
Michaelis, M., Vogel, C., Blenk, K.-H., & Jänig, W. (1997) · Pain · doi:10.1016/s0304-3959(97)00050-x · Cited by 52 · see citing works
Noxious heat‐induced CGRP release from rat sciatic nerve axons in vitro
Sauer, S. K., Reeh, P. W., & Bove, G. M. (2001) · European Journal of Neuroscience · doi:10.1046/j.0953-816x.2001.01741.x · Cited by 50 · see citing works
Self-citationSensory Transduction in Peripheral Nerve Axons Elicits Ectopic Action Potentials
Hoffmann, T., Sauer, S. K., Horch, R. E., & Reeh, P. W. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.1627-08.2008 · Cited by 48 · see citing works
Self-citationFischer, M. J. M., & Reeh, P. W. (2007) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2007.05582.x · Cited by 47 · see citing works
Self-citationSensitization of vanilloid receptor involves an increase in the phosphorylated form of the channel
Lee, S.-Y., Lee, J.-H., Kang, K.-K., Hwang, S., Choi, K. D., & Oh, U. (2005) · Archives of Pharmacal Research · doi:10.1007/bf02977669 · Cited by 46 · see citing works
Katanosaka, K., Banik, R. K., Girón, R., Higashi, T., Tominaga, M., & Mizumura, K. (2008) · Neuroscience Research · doi:10.1016/j.neures.2008.08.004 · Cited by 43 · see citing works
Stimulated prostaglandin E2 release from rat skin, in vitro
Sauer, S. K., Schäfer, D., Kress, M., & Reeh, P. W. (1998) · Life Sciences · doi:10.1016/s0024-3205(98)00176-3 · Cited by 36 · see citing works
Self-citationIrritant-Induced Chronic Cough: Irritant-Induced TRPpathy
Brooks, S. M. (2008) · Lung · doi:10.1007/s00408-007-9068-0 · Cited by 35 · see citing works
Cough Sensors. II. Transient Receptor Potential Membrane Receptors on Cough Sensors
Materazzi, S., Nassini, R., Gatti, R., Trevisani, M., & Geppetti, P. (2009) · Handbook of experimental pharmacology · doi:10.1007/978-3-540-79842-2_3 · Cited by 34 · see citing works
Bradykinin-induced nociceptor sensitisation to heat depends on cox-1 and cox-2 in isolated rat skin
Mayer, S., Izydorczyk, I., Reeh, P. W., & Grubb, B. D. (2006) · Pain · doi:10.1016/j.pain.2006.10.027 · Cited by 26 · see citing works
Self-citationSodium Channels in Primary Sensory Neurons: Relationship to Pain States
Wood, J. N., Akopian, A. N., Baker, M. D., Ding, Y., Geoghegan, F., Nassar, M. A., Malik‐Hall, M., Okuse, K., Poon, L., Ravenall, S., et al. (2001) · Novartis Foundation symposium · doi:10.1002/0470846682.ch11 · Cited by 22 · see citing works
Projected pain from noxious heat stimulation of an exposed peripheral nerve – A case report
Hoffmann, T., Sauer, S. K., Horch, R. E., & Reeh, P. W. (2008) · European Journal of Pain · doi:10.1016/j.ejpain.2008.09.014 · Cited by 15 · see citing works
Self-citationLang, P. M., Hilmer, V. B., & Grafe, P. (2007) · Anesthesiology · doi:10.1097/01.anes.0000278862.77981.c8 · Cited by 11 · see citing works
Jia, Y., & Lee, L. (2007) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2007.08.002 · Cited by 7 · see citing works
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- Authors
- Sauer, S. K., & Reeh, P. W.
- Affiliations
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Venue
- Digestive Diseases
- Publisher
- S. Karger AG
- Published
- 2009
- Volume
- 27
- Issue
- Suppl. 1
- Pages
- 11-15
- ISSN
- 0257-2753 (ISSN-L)
- 1421-9875
- OpenAlex
- W1986149771
- Cited by
- 9
- References
- 57
- Citations by year
- 2025: 1 · 2023: 1 · 2020: 2 · 2019: 2 · 2015: 1 · 2013: 1 · 2012: 1
- FWCI
- 0.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Digestive Diseases (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Health Sciences › Medicine › Psychiatry and Mental health › Migraine and Headache Studies
- Keywords
- axonal membrane, TRPV1, capsaicin receptor, calcitonin gene-related peptide release, bradykinin receptors, prostaglandin E receptors, anandamide, endocannabinoid system, neuropathic pain, spinal sensitization, allodynia, hyperalgesia, vagus nerve, visceral nociception, hypersensitivity
- MeSH terms
- Action Potentials, Animals, Axons, Humans, Hypersensitivity, Inflammation, Membranes, Sensation, TRPV Cation Channels
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